Document Detail

ABCB1 single nucleotide polymorphisms (1236C>T, 2677G>T, and 3435C>T) do not affect transport activity of human P-glycoprotein.
MedLine Citation:
PMID:  23619510     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: P-glycoprotein (P-gp) is a multidrug efflux transporter that has a defined role in the absorption and disposition of drugs. Many studies have investigated the potential influence of ABCB1 polymorphisms on the disposition of its substrates. However, there remains significant controversy regarding the role of these polymorphisms. Our aim was to generate a P-gp expression system for single nucleotide polymorphisms (SNPs) and the reference sequence to assess the functional significance of these variants on transport.
MATERIALS AND METHODS: P-gp reference, a P-gp ATPase deficient mutant (G534D) and a triple SNP variant of P-gp (1236C>T, 2677G>T, and 3435C>T) were expressed in Xenopus laevis oocytes and used to assess the influence of these SNPs on transport of digoxin and imatinib. The inhibition of P-gp-mediated transport in Caco-2 cells and oocytes was also assessed.
RESULTS: No effect of the triple SNP variant of P-gp on molecular transport of digoxin or imatinib was observed. The rank order of inhibition of P-gp in Caco-2 cells and ABCB1-injected oocytes was tariquidar>elacridar>PSC-833>laniquidar>cyclosporine>verapamil>dipyridamole.
CONCLUSION: These data suggest there is no functional consequence of these SNPs for molecular transport of model substrates or inhibition by model inhibitors for P-gp. Transporter-injected oocytes may be a useful tool for probing the mechanism for unexplained drug-drug interactions or to characterize therapeutic transport inhibitors.
David Dickens; Andrew Owen; Ana Alfirevic; Munir Pirmohamed
Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Pharmacogenetics and genomics     Volume:  23     ISSN:  1744-6880     ISO Abbreviation:  Pharmacogenet. Genomics     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-04-26     Completed Date:  2014-01-10     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  101231005     Medline TA:  Pharmacogenet Genomics     Country:  United States    
Other Details:
Languages:  eng     Pagination:  314-23     Citation Subset:  IM    
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MeSH Terms
Benzamides / metabolism
Biological Transport / genetics
Caco-2 Cells
Digoxin / metabolism
Haplotypes / genetics
Inhibitory Concentration 50
Mutant Proteins / metabolism
Oocytes / metabolism
P-Glycoprotein / genetics*
Piperazines / metabolism
Polymorphism, Single Nucleotide / genetics*
Pyrimidines / metabolism
Reproducibility of Results
Xenopus laevis
Grant Support
G0800247//Medical Research Council
Reg. No./Substance:
0/ABCB1 protein, human; 0/Benzamides; 0/Mutant Proteins; 0/P-Glycoprotein; 0/Piperazines; 0/Pyrimidines; 73K4184T59/Digoxin; BKJ8M8G5HI/imatinib

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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